The major anxiety disorders that are the public health focus of this proposal are moderately heritable, but, like most complex disorders, they present daunting targets for conventional gene mapping analysis. By comparison, certain innate and learned forms of fear present much more tractable targets for genetic analysis since they are highly conserved behaviors whose molecular genetic basis can be directly probed using mouse models. Fear conditioning is a particularly attractive target because the underlying neurocircuitry and associated information processing systems are relatively well characterized, and because the mouse behavioral paradigms can be closely mimicked in humans and analyzed as quantitative distributed traits. For reasons elaborated throughout this Program Project, we hypothesize that a subset of the genes that harbor genetic determinants for learned or innate forms of fear will also harbor susceptibility or protective alleles for human anxiety disorders. The strategy in Project 2 is to first identify genetic determinants for fear conditioning behavior in both mice and humans, and for other forms of innate fear in mice, and second to apply this knowledge to the genetic study of the major anxiety disorders in humans. Beginning with a small set of candidate genes that have been directly implicated in the acquisition or processing of learned fear (i.e., fear conditioning) (Project 1A; Kandel), or innate fear (Project 1B; Hen), we first propose genomic and bioinformatic strategies to identify and predict, respectively, additional networks of genes that regulate or mediate the genetically engineered changes in fear behaviors. Second, approximately 80-100 candidate genes will be selected from these studies and systematically surveyed for trait-related gene variants in a sample of ~900 random selected individuals scored for fear conditioning, anxiety dimensions, and multivariate, composite anxiety phenotypes (Project 3: Fyer). When trait alleles are predicted for fear, anxiety, or composite anxiety phenotypes, they will be evaluated as susceptibility alleles for human anxiety disorders (Project 4; Weissman).